Articles: gaba-modulators-pharmacology.
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Biochemical pharmacology · Feb 2015
GABAA α5 subunit-containing receptors do not contribute to reversal of inflammatory-induced spinal sensitization as indicated by the unique selectivity profile of the GABAA receptor allosteric modulator NS16085.
GABAA receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain. Restoration of diminished spinal GABAA-α2 and -α3 subunit-containing receptor function is a principal contributor to this analgesia, albeit involvement of GABAA-α5-receptors has not been excluded. Thus, we compared NS11394 and TPA023 (PAMs with selectivity/efficacy at GABAA-α2/α3/α5 receptors) with TP003 (a reportedly GABAA-α3 selective PAM) against spinal sensitization. ⋯ In adult rats, NS16085 (3-30 mg/kg, p.o.) dose-dependently reduced formalin-induced hindpaw flinching with efficacy comparable to NS11394. Thus, potentiation of GABAA-α2 and-α3 receptors is sufficient to depress spinal sensitization and mediate analgesia after inflammatory injury. Positive modulation at GABAA-α5-receptors is apparently dispensable for this process, an important consideration given the role of this receptor subtype in cognitive function.
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Advances in pharmacology · Jan 2015
ReviewAllosteric modulation of GABAA receptors via multiple drug-binding sites.
GABAA receptors are ligand-gated ion channels composed of five subunits that can be opened by GABA and be modulated by multiple pharmacologically and clinically important drugs. Over the time, hundreds of compounds from different structural classes have been demonstrated to modulate, directly activate, or inhibit GABAA receptors, and most of these compounds interact with more than one binding site at these receptors. Crystal structures of proteins and receptors homologous to GABAA receptors as well as homology modeling studies have provided insights into the possible location of ligand interaction sites. ⋯ The existence of multiple GABAA receptor subtypes with distinct subunit composition, the contribution of distinct subunit sequences to binding sites of different receptor subtypes, as well as the observation that even subunits not directly contributing to a binding site are able to influence affinity and efficacy of drugs, contribute to a unique pharmacology of each GABAA receptor subtype. Thus, each receptor subtype has to be investigated to identify a possible subtype selectivity of a compound. Although multiple binding sites make GABAA receptor pharmacology even more complicated, the exploitation of ligand interaction with novel-binding sites also offers additional possibilities for a subtype-selective modulation of GABAA receptors.
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Anesthesia and analgesia · Dec 2014
Enhancement of α5-Containing γ-Aminobutyric Acid Type A Receptors by the Nonimmobilizer 1,2-Dichlorohexafluorocyclobutane (F6) Is Abolished by the β3(N265M) Mutation.
Modulation of γ-aminobutyric acid type A receptors (GABAARs) by general anesthetics may contribute to their ability to produce amnesia. Receptors containing α5 subunits, which mediate tonic and slow synaptic inhibition, are co-localized with β3 and γ2 subunits in dendritic layers of the hippocampus and are sensitive to low (amnestic) concentrations of anesthetics. Because α5 and β3 subunits influence performance in hippocampus-dependent learning tasks in the presence and absence of general anesthetics, and the experimental inhaled drug 1,2-dichlorohexafluorocyclobutane (F6) impairs hippocampus-dependent learning, we hypothesized that F6 would modulate receptors that incorporate α5 and β3 subunits. We hypothesized further that the β3(N265M) mutation, which controls receptor modulation by general anesthetics, would similarly influence modulation by F6. ⋯ The nonimmobilizer F6 modulates GABAARs in a manner that depends on subunit composition and mode of receptor activation by GABA, supporting a possible role for α5-containing receptors in suppression of learning and memory by F6. Furthermore, common structural requirements indicate that similar molecular mechanisms may be responsible for the enhancing effects of F6 and conventional general anesthetics.
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Drug Alcohol Depend · Oct 2014
Controlled Clinical TrialSeparate and combined effects of the GABAA positive allosteric modulator diazepam and Δ⁹-THC in humans discriminating Δ⁹-THC.
Our previous research suggested the involvement of γ-aminobutyric acid (GABA), in particular the GABAB receptor subtype, in the interoceptive effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC). The aim of the present study was to determine the potential involvement of the GABAA receptor subtype by assessing the separate and combined effects of the GABAA positive allosteric modulator diazepam and Δ(9)-THC using pharmacologically selective drug-discrimination procedures. ⋯ These results suggest that the GABAA receptor subtype has minimal involvement in the interoceptive effects of Δ(9)-THC, and by extension cannabis, in humans.
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The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species. ⋯ DORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.